Cancer is a leading cause of death in the United States, second only to heart disease, killing more than half a million Americans per year. Importantly, many of these cancer-related deaths are thought to be preventable if improved methods for early detection of the disease can be developed. One method of detection of the disease is imaging cancer cells or tumors by radiographraphy or photoluminescence (e.g. fluorescence). However, most methods for cancer tumor imaging either lack the sensitivity to detect early malignant loci or do not distinguish between tumor masses and sites of inflammation. For example, 18F-fluorodeoxyglucose (18F-FDG) not only effectively images cancer, but also accumulates at sites of infection and immune-mediated inflammation, complicating the determination of whether an imaged mass derives from a tumor or inflamed tissue (e.g. rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, and the like). Folate uptake by cancer cells and activated macrophages involves different isoforms of the same receptor (i.e. FR-α and FR-β, respectively). These two isoforms are only 76% homologous and structural differences between the two isoforms might allow selective binding. Consequently, there is a need for targeting ligands with increased selectivity for either FR-α or FR-β. Folate receptor binding ligands with increased selectivity for folate receptor-α have been discovered that are useful for preferential targeting of folate receptor ligand binding conjugates to cells expressing, over-expressing, or selectively expressing FR-α. Illustratively, an N5,N10-dimethylated derivative of tetrahydrofolic acid (DMTHF) displays increased selectivity for FR-α over FR-β. It has also been found that a 99mTc chelate conjugate of DMTHF allows selective imaging of cancer tissue in animals containing both solid tumors and one of multiple types of inflammatory disease.
In one embodiment of the invention, a folate receptor alpha selective binding ligand drug conjugate of the formulaB-L-Dor a pharmaceutically acceptable salt thereof, wherein
B is a folate receptor alpha selective binding ligand;
L is a linker or is absent; and
D represents one or more drugs independently selected from the group consisting of a diagnostic agent, a therapeutic agent, and a imaging agent is described.
In another embodiment, a pharmaceutical composition is described comprising an imaging effective or therapeutically effective amount of one or more of the folate receptor alpha selective binding ligand drug conjugates described herein.
In another embodiment, a method for imaging cancer cells in a patient is described, the method comprising administering an imaging effective amount of any one of the folate receptor alpha selective binding ligand drug conjugates described herein to the patient; and imaging the cancer cells.
In another embodiment, a method for treating a patient in need of relief from cancer is described, the method comprising the step of administering to the patient a therapeutically effective amount of any one or more of the folate receptor alpha selective binding ligand drug conjugates described herein.